Natriuretic Peptides as Multisystem Regulators: From Clinical Biomarkers to Therapeutic Targets in Cardio-immunology

Natriuretic peptides (NPs) ANP, BNP, and CNP extend beyond biomarkers of wall stress to regulators of cardiovascular, renal, metabolic, and immune pathways via cGMP-PKG signaling. We synthesize mechanistic and translational evidence, highlight NP "resistance," and appraise therapeutic strategies that augment NP signaling.

Narrative review integrating human physiology, preclinical studies, and key trials (e.g., PARADIGM-HF, PARAGON-HF, EMPEROR-Preserved), plus emerging agents (ARNIs, designer peptides, NPR-C modulation, receptor sensitizers).

NPs exert natriuretic, vasodilatory, antifibrotic, and immunomodulatory effects. Resistance via neprilysin degradation, NPR-C-mediated clearance, and receptor desensitization blunts efficacy in advanced disease. ARNIs improve outcomes in HFrEF; benefits in HFpEF are subgroup-dependent. NP biology intersects with metabolic and inflammatory circuits, suggesting potential synergy with SGLT2 inhibitors and other modulators.

NPs are promising therapeutic targets across cardio-renal-metabolic spectra, but for many strategies, the evidence remains preclinical or early-phase. We propose a translational roadmap emphasizing mechanistic validation, responder phenotyping, and rigorously powered trials to test NP augmentation (and combinations) in HFrEF, obesity-related HFpEF, pulmonary vascular disease, and immune-cardiometabolic syndromes.